In producing drugs, control of crystal polymorphs of chemical substances, the bulk powder, is recognized as an important matter because a difference in the polymorphs has a great influence on the properties as a drug such as a pharmaceutical function, bioavailability, stability, and the like. This is as stated in the ICH (International Conference on Harmonisation) Q6A guideline, “Specifications: Test Procedure and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances.”
With regard to the polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid, PTL 1 discloses presence of 5 kinds of polymorphs, including A-form crystals, B-form crystals, C-form crystals, D-form crystals, and G-form crystals, as well as an amorphous material. Also disclosed are methods for producing the same. The methods for producing the polymorphs disclosed herein are for producing each of the polymorphs, comprising: adding a predetermined amount of a mixed solvent of methanol or 2-propanol and water to 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid; dissolving the mixture by stirring under heat; setting the methanol/water composition and the like and temperature to predetermined values by addition of water and cooling; and thereafter collecting crystals by filtration and drying the same.
However, influences of the initial concentration referred to in PTL 1 are only on the chemical purity and the amounts of the recovered product, and effects on the polymorphs obtained are not described. In addition, in the case of crystallization from a mixed solvent of 2-propanol and water, it is only described that the G-form crystals are obtained.
Furthermore, at International Symposium on Industrial Crystallization (Sep. 21-25, 1998, Tianjin, China), M. Kitamura, M. Hanada, K. Nakamura, and others have shown in “Crystallization and transformation behavior of the polymorphs of thiazole-derivative” (see NPL 1) that, under the condition of a methanol/water composition and temperature where only the A-form crystals were thought to be obtained, the G-form crystals or a mixture of the A-form crystals and the G-form crystals were obtained in some cases at the time of crystallization, when water addition time was drastically changed substantially. In addition, they have also shown that, by subsequently changing the temperature of the crystallization liquid and by keeping the liquid in a state of agitation, the crystals were transformed to the D-form crystals.
When industrially useful A-form crystals are to be produced, these heretofore known methods are not pronounced to be completely free from contamination by the G-form crystals. Moreover, in order to avoid contamination by the G-form crystals, the water addition time is restricted and, thus, there is also a problem that a long time is required for industrial production.
Meanwhile, PTL 2 discloses a method for producing the polymorphs by addition of water to 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid dissolved in methanol or a mixed solvent of methanol/water, wherein the initial concentrations and water addition time are varied to obtain the A-form crystals, the G-form crystals, or a mixture of A-form and the G-form crystals of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid.
However, crystallization using these heretofore known mixed solvent systems, for example crystallization using a mixed solvent system of methanol/water with a ratio of 7/3 provides crystals of a form different from the A-form crystals or a mixture of A-form crystals and crystals of a form different therefrom. Thus, it has not been possible to obtain the A-form crystals stably.